FBXW7 is a tumor suppressor gene on human chromosome 4q that encodes the substrate recognition components of SKP1Cullin1F-box protein-ubiquitin E3 ligase complexes and one of the most commonly mutated genes in cancer. Early studies showed that nearly three-quarters of the mutations are missense point mutations that cause amino acid substitutions in key residues that form the substrate-binding interface four arginine residues R465, R479, R505 (Fbw7ARG), and are hotspots. Studies of cancers of diverse tissue origins suggested that FBXW7 mutations occurred in approximately 6% of all tumors. The most commonly affected tumors were cholangiocarcinoma (35%), (T-cell acute lymphocytic leukemia, 31%), endometrial cancer (9%), gastric cancer (6%) and colorectal cancer (6-10%). Studying these hotspot mutations is of very much relevance to cancer biology since FBXW7ARG mutations have a profound effect on substrate-binding affinity compared with other missense mutations and also proteomics analysis will provide some new substrates that could be strongly associated with an oncogenic function of these mutations. Further characterizing arginine mutation in carcinogenesis using mouse genetics will strengthen our study and provide us a clue for therapeutic options. For mouse studies, we will cross mutant FBXW7 R468 mice with p53(-/-) mice and then progenies will be mated with Tamoxifen inducible UBC-cre mice for incidences of tumor formation in widespread tissues. Later we will create tumors in an organ-specific manner (Head and Neck, Lung, and colorectal) in FBXW7 R465 mice and FBXW7 R465 specific drugs will be induced to study the therapeutics. We have achieved following goals in this project: We got some novels target to study from mass spectroscopy experiments. We have got mice with both FBXW7R468 and P53 R175H. Currently we are mating B6- FBXW7R468(+/-) P53 (+/-) with UBC-cre mice.